Mutational hotspots in the mitochondrial genome of lung cancer |
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Authors: | Choi So-Jung Kim Sung-Hyun Kang Ho Y Lee Jinseon Bhak Jong H Sohn Insuk Jung Sin-Ho Choi Yong Soo Kim Hong Kwan Han Jungho Huh Nam Lee Gyusang Kim Byung C Kim Jhingook |
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Institution: | aDepartment of Oral Cell Biology, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and VU University Amsterdam, Research Institute MOVE, Amsterdam, The Netherlands;bTNO Quality of Life, Biosciences, Leiden, The Netherlands;cDepartment of Orthopaedics, VU Medical Center, Research Institute MOVE, Amsterdam, The Netherlands |
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Abstract: | In lung fibrosis tissue architecture and function is severely hampered by myofibroblasts due to excessive deposition of extracellular matrix and tissue contraction. Myofibroblasts differentiate from fibroblasts under the influence of transforming growth factor (TGF) β1 but this process is also controlled mechanically by cytoskeletal tension. In healthy lungs, the cytoskeleton of fibroblasts is mechanically strained during breathing. In stiffer fibrotic lung tissue, this mechanical stimulus is reduced, which may influence fibroblast-to-myofibroblast differentiation. Therefore, we investigated the effect of cyclic mechanical stretch on fibroblast-to-myofibroblast differentiation.Primary normal human lung fibroblasts were grown on BioFlex culture plates and stimulated to undergo myofibroblast differentiation by 10 ng/ml TGFβ1. Cells were either or not subjected to cyclic mechanical stretch (sinusoidal pattern, maximum elongation 10%, 0.2 Hz) for a period of 48 h on a Flexercell apparatus. mRNA expression was analyzed by real-time PCR.Cyclic mechanical loading reduced the mRNA expression of the myofibroblast marker α-smooth muscle actin and the extracellular matrix proteins type-I, type-III, and type-V collagen, and tenascin C. These outcomes indicate that fibroblast-to-myofibroblast differentiation is reduced. Cyclic mechanical loading did not change the expression of the fibronectin ED-A splice variant, but did decrease the paracrine expression of TGFβ1, thereby suggesting a possible regulation mechanism for the observed effects. The data suggest that cyclic loading experienced by healthy lung cells during breathing may prevent fibroblasts from differentiating towards myofibroblasts. |
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Keywords: | Myofibroblast Differentiation TGFβ1 Lung fibrosis Cyclic mechanical loading |
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